2-hydroxy-2-phenylthiophenylpropionamides as androgen receptor modulators

Abstract

Compounds of structural formula (I) are modulators of the androgen receptor (AR) in a tissue selective manner. These compounds are useful in the enhancement of weakened muscle tone and the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HFV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), abdominal adiposity, metabolic syndrome, type II diabetes, cancer cachexia, Alzheimer's disease, muscular dystrophies, cognitive decline, sexual dysfunction, sleep apnea, depression, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

1 . A compound of structural formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 one of X, Y, and Z is —N or —NO, and the other two moieties are —CH; 
 n is 0, 1, 2, or 3; 
 
       
         
           
           
               
               
           
         
       
       is phenyl or thiophenyl;
 R 1  is chosen from
 perfluoroC 1-6 alkyl, 
 perfluoroC 1-6 alkoxy, 
 C 1-10  alkyl, 
 C 2-10  alkenyl, 
 C 2-10  alkynyl, 
 aryl C 1-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkyl, 
 hydroxycarbonyl C 0-10  alkyl, 
 hydroxycarbonyl C 2-10  alkenyl, 
 hydroxycarbonyl C 2-10  alkynyl, and 
 hydroxy C 0-10 alkyl; 
 
 R 2  is chosen from
 cyano, 
 amino, 
 hydroxy C 0-10 alkyl, 
 perfluoroC 1-6 alkyl, 
 perfluoroC 1-6 alkoxy, 
 aryl C 1-10  alkyl, 
 C 3-8  cycloalkyl C 10  alkyl, 
 C 3-8  heterocyclyl C 1-10  alkyl, 
 C 3-8  heterocycloalkyl C 1-10 alkyl, 
 (C 0-10  alkyl) 1-2 amino C 0-10  alkyl, 
 (aryl C 0-10  alkyl) 1-2 amino C 0-10  alkyl, 
 (C 3-8  cycloalkyl C 0-1  alkyl)-2amino C 0-10  alkyl, 
 (C 3-8  heterocyclyl C 0-10  alkyl) 1-2 amino C 0-10  alkyl, 
 (C 3-8  heterocycloalkyl C 1-10  alkyl) 1-2 amino C 0-10  alkyl, 
 (C 0-10  alkyl) 1-2 aminocarbonyloxy C 0-10  alkyl, 
 (aryl C 0-10  alkyl) 1-2 aminocarbonyloxy C 0-10  alkyl, 
 (C 3-8  cycloalkyl C 1-10  alkyl) 1-2 aminocarbonyloxy C 0-10  alkyl, 
 (C 3-8  heterocyclyl C 0-10  alkyl) 1-2 aminocarbonyloxy C 0-10  alkyl, 
 (C 3-8  heterocycloalkyl C 0-10  alkyl) 1-2 aminocarbonyloxy C 0-10  alkyl, 
 C 0-10  alkylcarbonyloxy C 0-10  alkyl, 
 aryl C 0-10  alkylcarbonyloxy C 0-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkylcarbonyloxy C 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkylcarbonyloxy C 0-10  alkyl, 
 C 3-8  heterocycloalkyl C 0-10  alkylcarbonyloxy C 0-10  alkyl, 
 (C 0-10  alkyl) 1-2 aminocarbonylaminoC 0-10  alkyl, 
 (aryl C 0-10  alkyl) 1-2 aminocarbonylamino C 0-10  alkyl, 
 (C 3-8  cycloalkyl C 0-10  alkyl) 1-2 aminocarbonylamino C 0-10  alkyl, 
 (C 3-8  heterocyclyl C 0-10  alkyl) 1-2 aminocarbonylamino C 0-10  alkyl, 
 (C 3-8  heterocycloalkyl C 0-10  alkyl) 1-2 aminocarbonylamino C 0-10  alkyl, 
 (C 0-10  alkyl) 1-2 aminocarbonyl C 0-10  alkyl, 
 (aryl C 0-10  alkyl) 1-2 aminocarbonyl C 0-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkylaminocarbonyl C 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkylaminocarbonyl C 0-10  alkyl, 
 C 3-8  heterocycloalkyl C 0-10  alkylaminocarbonyl C 0-10  alkyl, 
 C 0-10  alkyl carbonylamino C 0-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkyl carbonylamino C 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkyl carbonylamino C 0-10  alkyl, 
 C 3-8  heterocycloalkyl C 0-10  alkyl carbonylamino C 0-10  alkyl, 
 aryl C 0-10  alkyl carbonylamino C 0-10  alkyl, 
 C 0-10  alkyloxy carbonylamino C 0-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkyloxy carbonylamino C 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkyloxy carbonylamino C 0-10  alkyl, 
 C 3-8  heterocycloalkyl C 0-10  alkyloxy carbonylamino C 0-10  alkyl, 
 aryl C 0-10  alkyloxy carbonylamino C 0-10  alkyl, 
 C 0-10  alkyloxy carbonyloxy C 0-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkyloxy carbonyloxy C 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkyloxy carbonyloxy C 0-10  alkyl, 
 C 3-8  heterocycloalkyl C 0-10  alkyloxy carbonyloxy C 0-10  alkyl, 
 aryl C 0-10  alkyloxy carbonyloxy C 0-10  alkyl, 
 C 1-10  alkoxy (carbonyl) 0-1 C 0-10  alkyl, 
 C 0-10  alkylcarboxy C 0-10  alkylamino, 
 C 1-10 alkyloxy C 0-10 alkyl, 
 aryloxy C 0-10  alkyl, 
 C 3-8  cycloalkyloxy C 0-10  alkyl, 
 C 3-8  heterocyclyloxy C 0-10  alkyl, 
 C 3-8  heterocyclylC 0-10 alkyloxy C 0-10  alkyl. 
 C 1-10  alkylcarbonyloxy C 0-10  alkyl, 
 C 1-10  alkyloxy(carbonyl) 0-1 C 0-10  alkylamino, 
 C 3-8  heterocyclyl C 0-10  alkyloxy(carbonyl) 0-1 C 0-10  alkylamino, 
 C 3-8  heterocycloalkyl C 0-10  alkyloxy(carbonyl) 0-1 C 0-10  alkylamino, 
 C 3-8  cycloalkyl C 0-10  alkyloxy(carbonyl) 0-1 C 0-10  alkylamino, and 
 aryl C 0-10  alkyloxy(carbonyl) 0-1 C 0-10  alkylamino; 
 
 R 3  is chosen from
 hydrogen, 
 halogen, 
 perfluoroC 1-6 alkyl, 
 perfluoroC 1-6 alkoxy, 
 C 1-10  alkyl, 
 C 2-10  alkenyl, 
 C 2-10  alkynyl, 
 aryl C 0-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkyl, 
 (C 0-10  alkyl) 1-2 aminocarbonyl C 0-10  alkyl, 
 (aryl C 0-10 alkyl) 1-2 aminocarbonyl C 0-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkyl aminocarbonyl C 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkyl aminocarbonyl C 0-10  alkyl, 
 C 0-10  alkyl carbonylamino C 10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkyl carbonylamino C 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkyl carbonylamino C 1-10  alkyl, 
 aryl C 0-10  alkyl carbonylamino C 1-10  alkyl, 
 C 0-10  alkyloxy carbonylamino C 1-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkyloxy carbonylamino C 10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkyloxy carbonylamino C 1-10  alkyl, 
 aryl C 0-10  alkyloxy carbonylamino C 1-10  alkyl, 
 C 1-10  alkoxy (carbonyl) 0-1 C 0-10 alkyl, 
 C 0-10  alkyloxy carbonylC 0-10  alkyl, 
 C 3-8  cycloalkyl C 0-10  alkyloxy carbonylC 0-10  alkyl, 
 C 3-8  heterocyclyl C 0-10  alkyloxy carbonylC 0-10  alkyl, 
 aryl C 0-10  alkyloxy carbonylC 0-10  alkyl, 
 hydroxycarbonyl C 1-10  alkyl, 
 hydroxycarbonyl C 2-10  alkenyl, 
 hydroxycarbonyl C 2-10  alkynyl, and 
 hydroxy C 0-10 alkyl; 
 
 wherein in R 1 , R 2 , and R 3 , said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocycloalkyl, and cycloalkyl are each optionally substituted with one or more groups chosen from hydroxy, C 1-6  alkyl, C 1-6  alkoxy, halogen, CO 2 H, cyano, O(C═O)C 1 -C 6  alkyl, NO 2 , trifluoromethoxy, trifluoroethoxy, —O (0-1) (C 1-10 )perfluoroalkyl, C 0-10  alkylaminocarbonylamino, C 1-10  alkyloxycarbonylamino, C 1-10  alkylcarbonylamino, C 0-10  alkylaminosulfonylamino, C 1-10  alkylsulfonylamino, C 1-10  alkylsulfonyl, C 0-10  alkylaminosulfonyl, C 0-10  alkylaminocarbonyl and NH 2 . 
 
     
     
         2 . A compound of  claim 1 , chosen from: 
       (2R)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-2-phenylpropanamide; 
       (2R)-3,3,4,4,4-pentafluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-2-phenylbutanamide; 
       (2S)-3,3,4,4,4-pentafluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-2-phenylbutanamide; 
       (2R)-2-(4-chloro-3-fluorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2S)-2-(4-chloro-3-fluorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2R)-2-(3,4-difluorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2S)-2-(3,4-difluorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2R)-2-(4-fluorophenyl)-3,3,3-trifluoro-2-hydroxy-yl-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2S)-2-(4-fluorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2R)-2-(4-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2S)-2-(4-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2R)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-2-[3-(trifluoromethyl)phenyl]propanamide; 
       (2S)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-2-[3-(trifluoromethyl)phenyl]propanamide; 
       (2R)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2S)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2R)-3,3,3-trifluoro-2-hydroxy-2-[3-(methylthio)phenyl]-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2S)-3,3,3-trifluoro-2-hydroxy-2-[3-(methylthio)phenyl]-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide; 
       (2R)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-2-(2-thienyl)propanamide; 
       (2S)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-2-(2-thienyl)propanamide; 
       2-(5-bromo-2-thienyl)-3,3,3-trifluoro-2-hydroxy-N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]propanamide, 
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . Method of treating a condition selected from the group consisting of weakened muscle tone, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia, hematopoietic disorders, arthritic condition and joint repair, HIV-wasting, prostate cancer, cancer cachexia, muscular dystrophies, Alzheimer's disease, cognitive decline, sexual dysfunction, sleep apnea, benign prostate hyperplasia, abdominal adiposity, metabolic syndrome, type II diabetes, depression, premature ovarian failure, and autoimmune disease, in a mammal in need thereof comprising administering to a patient in need of such treatment a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A method according to  claim 3 , wherein said condition is osteoporosis. 
     
     
         5 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         6 . A composition of  claim 5 , further comprising an active ingredient selected from: an estrogen or an estrogen derivative, alone or in combination with a progestin or progestin derivative, a bisphosphonate, an antiestrogen or a selective estrogen receptor modulator, an αvβ3 integrin receptor antagonist, a cathepsin K inhibitor, n HMG-CoA reductase inhibitor, an osteoclast vacuolar ATPase inhibitor, an antagonist of VEGF binding to osteoclast receptors, an activator of peroxisome proliferator-activated receptor γ, calcitonin, a calcium receptor antagonist, parathyroid hormone or analog thereof, a growth hormone secretagogue, human growth hormone, insulin-like growth factor, a p38 protein kinase inhibitor, bone morphogenetic protein, an inhibitor of BMP antagonism, a prostaglandin derivative, vitamin D or vitamin D derivative, vitamin K or vitamin K derivative, ipriflavone, fluoride salts, dietary calcium supplements, osteoprotegerin, an alpha-1 adrenergic blocking agent, and a 5 alpha reductase inhibitor. 
     
     
         7 . A composition of  claim 6 , wherein said bisphosphonate is alendronate. 
     
     
         8 . A process for making a pharmaceutical composition comprising combining a compound according to  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier. 
     
     
         9 . The method of  claim 3 , wherein the arthritic condition is selected from rheumatoid arthritis and osteoarthritis. 
     
     
         10 . The method of  claim 3 , wherein the condition is selected from condition selected from: weakened muscle tone, sarcopenia, and cancer cachexia.